Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis

Valeriya Gaysinskaya, Susan E. Stanley, Soheir Adam, Mary Armanios

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. Research Question: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? Study Design and Methods: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. Results: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. Interpretation: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)2449-2457
Number of pages9
JournalCHEST
Volume158
Issue number6
DOIs
StatePublished - Dec 2020

Keywords

  • bone marrow failure
  • lung transplantation
  • telomerase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

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